Whenever a patient with a profound immunodeficiency (primary, secondary, or iatrogenic) receives a graft of an organ rich in immunocompetent cells there is a considerable risk that a graft-versus-host reaction may develop. Such reactions are a significant problem in infants and children with primary immunodeficiencies on whom a bone marrow transplant is performed with the goal of reconstituting the immune system and in patients receiving a bone marrow transplant for the treatment of malignancy. Many patients receiving bone marrow transplants have received cytotoxic/immunosuppressive therapy and their immune system is completely or partially destroyed.
Allogeneic bone marrow transplants have been demonstrated to be of use in curing patients with hematological malignancies, aplastic anemia, and congenital immunodeficiency and metabolic diseases. Allogeneic bone marrow transplant involves the transfer of hematopoeitic and immunocompetent lymphoid elements from a donor into a recipient. The transfer is preceded by bone marrow ablative high-dose chemotherapy and radiation therapy aimed at eliminating the recipient's underlying malignancy and/or at suppressing the recipient's immune system (to prevent rejection of the foreign tissue). The recipient's bone marrow is then repopulated with donor stem cells. These donor cells also lead to reconstitution of the recipient's immune system.
The major complication of allogeneic bone marrow transplant has been the development of graft-versus-host disease (GVHD) mediated by donor T lymphocytes that attack tissues (mainly skin, gastrointestinal tract, and liver) of the recipient. Graft-versus-host disease can be manifested both acutely (within weeks of transplant) or chronically (lasting from months to years after bone marrow transplant and usually following acute graft-versus-host disease). Acute graft-versus-host disease is manifested by a maculopapular, erythematous rash, diarrhea, and hepatitis. Immune reconstitution is also impaired resulting in a prolonged severe immunosuppression. Chronic graft-versus-host disease resembles autoimmune disorders in the development of sclerotic and mucous membrane and skin changes, pulmonary fibrosis and immune-mediated hemolytic anemia and thrombocytopenia. T cell depletion techniques, drugs such as prednisone and cyclosporine A (CSA) and toxin-linked antibodies directed against T cells have been used with moderate success to prevent or ameliorate acute graft-versus-host disease. Unfortunately, treatment of chronic graft-versus-host disease which occurs in thirty to sixty per cent of patients has been much less successful. Also, the treatments of acute graft-versus-host disease discussed above are limited by toxicities, including hypertension, decreased renal function and most importantly, an increase in the ability of the recipient's immune system to reject the bone marrow graft and an increased incidence of leukemic relapse (associated with T cell depletion).
Once a graft-versus-host reaction is initiated, its control may be extremely difficult. Cyclosporine A administration has met with some success, both in therapy and in prophylaxis. Patients treated with cyclosporine A have less frequent and less severe episodes of graft-versus-host disease. However, cyclosporine A is nephrotoxic, causes hypertension and has been associated with accelerated atherosclerosis particularly in heart transplants. The most efficient approach to the prevention of graft-versus-host disease is to eliminate T cells from the graft. The major problem with this approach is that the transplant of T-cell depleted bone marrow into immunosuppressed adults results in a persistently profound state of severe immunodeficiency with increased incidence of opportunistic infections and also in a higher incidence of leukemic relapse.
U.S. Pat. No. 4,657,763 discloses the use of combinations of gold salts and hydroxychloroquine for treating autoimmune disease such as rheumatoid arthritis. This patent also discloses that the combination of drugs can be used to prevent rejection of organ transplants such as heart and kidney transplants. However, there is no suggestion that hydroxychloroquine is itself effective for this purpose in the absence of gold salts.
In view of the drawbacks associated with known methods of reducing or preventing graft-versus-host disease there exists a real need for methods of treating this disease that can be administered for long periods of time without severe side effects and that reduce the need for T cell depletion of the donor bone marrow cells.